Artificial sweeteners (non-nutritive sweeteners, NNS) are 100-20,000 times sweeter than sucrose and provide sweet taste with no or few calories. Consumption of NNS has steadily increased in both children and adults in the US. This trend will likely continue, since sugar intake has been linked to the development of obesity, and NNS offer a palatable alternative. However, several epidemiologic studies have suggested adverse metabolic effects of NNS resulting in similar consequences as high sugar intake, including weight gain, insulin resistance, fatty liver disease, diabetes and cardiovascular disease. In a previous pilot study, we observed that diet soda (Diet Rite Cola) augmented glucose-stimulated GLP-1 secretion in young, healthy volunteers. We then showed that the combination of 2 NNS (sucralose and acesulfame-potassium) in diet soda was partially responsible for the observed increase in GLP-1, but that the taste of diet soda or other ingredients also played a role. Furthermore, we found that insulin secretion was slightly higher when study participants received NNS (either in water or in diet soda) immediately before an OGTT compared to water as a pretreatment. We speculate that this may be due to pancreatic beta cell sweet taste receptor activation. We are also studying the effects of NNS in individuals who have undergone bariatric surgery (Roux-en-Y) since these persons have very high incretin concentrations, which may be important for their weight loss and lack of weight regain. It is unknown whether NNS can further induce GLP-1 responses. Additionally, we are testing the effects of the sweet taste receptor inhibitor lactisole on GLP-1 secretion. In collaboration with the University of Oklahoma, we quantified NNS concentrations in breast milk after a known exposure (diet soda) of mothers and repeated breast milk sampling for 6 hours. In another collaboration with the University of Chicago, we are investigating whether NNS plasma concentrations can explain the varying insulin secretory responses observed in the study participants. Since NNS are frequently consumed in combination with prescription medications, it is important to find out whether there are possible NNS-drug interactions. This hypothesis is based on a rodent study, in which sucralose increased the activity of P-glycoprotein (P-gp), a membrane transporter involved in absorption and distribution of a wide range of pharmacologic compounds, and CYP3A, a cytochrome P-450 enzyme important to the first-pass metabolism of many drugs. So far, experimental NNS effects in humans were mostly observed after acute (one time) or short-term exposure. In the above mentioned pharmacokinetic study, we administer sucralose orally for 4 weeks to overweight and obese African American and Hispanic women (in a parallel design, randomized, double blind study). By obtaining subcutaneous fat tissue (pre- and post-sucralose exposure), we will have the opportunity to investigate whether this sweetener upregulates inflammatory cytokines. We will also determine whether the described hormonal responses persist after prolonged compared to acute exposure.